Quinolones have been shown to be effective to varying degrees against a range of certain respiratory tract pathogens. However, as diseases caused by these pathogens are on the rise, there exists a need for antimicrobial compounds that are more potent and that exhibit a longer post-antibiotic effect than the present group of quinolones.
Gemifloxacin mesylate (SB-265805) is a novel fluoroquinolone useful as a potent antibacterial agent. Gemifloxacin compounds are described in detail in patent application PCT/KR98/00051 published as WO 98/42705. Patent application EP 688772 discloses novel quinoline(naphthyridine)carboxylic acid derivatives, including anhydrous (R,S)-7-(3-aminomethyl-4-methoxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid of formula I. 
PCT/KR98/00051 discloses (R,S)-7-(3-aminomethyl-4-syn-methoxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid methanesulfonate and hydrates thereof including the sesquihydrate.
Provided herein is an invention based, in part, on a significant discovery made using a gemifloxacin compound against a range of variety of Legionella isolated from nosocomial or acquired respiratory tract infections and from environmental sources, demonstrating the activity of the gemifloxacin compound used was superior to a number of quinolones as described in more detail herein. Gemifloxacin compounds are valuable compounds for the treatment of diseases caused by or related to atypical respiratory tract pathogens, thereby filling an unmet medical need.
An object of the invention is a method for modulating metabolism of atypical upper respiratory pathogenic bacteria comprising the step of contacting atypical upper respiratory pathogenic bacteria with an antibacterially effective amount of a composition comprising a gemifloxacin compound, or an antibacterially effective derivative thereof.
A further object of the invention is a method wherein said atypical upper respiratory pathogenic bacteria is selected from the group consisting of: a member of the genus Legionella, a member of the genus, Pseudomonas, Pseudomonas aeruginosa strain, a Legionella pneumophila strain, a Legionella pneumophila serogroup 1, a Legionella pneumophila serogroup 2, a Legionella pneumophila serogroup 3, a Legionella pneumophila serogroup 4, a Legionella pneumophila serogroup 5, a Legionella pneumophila serogroup 6, a Legionella pneumophila serogroup 7, a Legionella pneumophila serogroup 8, a Legionella dumoffli strain, a Legionella longbeacheae strain, a Legionella micdadei strain, a Legionella oakridgensis strain, a Legionella feelei strain, a Legionella anisa strain, a Legionella sainthelensi strain, a Legionella bozemanii strain, a Legionella gormanii strain, a Legionella wadsworthii strain, a Legionella jordanis strain and a Legionella gormanii strain.
Also provided by the invention is a method of treating or preventing a bacterial infection by atypical upper respiratory pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a gemifloxacin compound to a mammal suspected of having or being at risk of having an infection with atypical upper respiratory pathogenic bacteria.
A preferred method is provided wherein said modulating metabolism is inhibiting growth of said bacteria or killing said bacteria.
A further preferred method is provided wherein said contacting said bacteria comprises the further step of introducing said composition into a mammal, particularly a human.
Further preferred methods are provided by the invention wherein said bacteria is selected from the group consisting of: a member of the genus Legionella, a member of the genus, Pseudomonas, Pseudomonas aeruginosa strain, a L. pneumophila strain, a L. pneumophila serogroup 1, a L. pneumophila serogroup 2, a L. pneumophila serogroup 3, a L. pneumophila serogroup 4, a L. pneumophila serogroup 5, a L. pneumophila serogroup 6, a L. pneumophila serogroup 7, a L. pneumophila serogroup 8, a L. dumoffii strain, a L. longbeacheae strain, a L. micdadei strain, a L. oakridgensis strain, a L. feelei strain, a L. anisa strain, a L. sainthelensi strain, a L. bozemanii strain, a L. gormanii strain, a L. wadsworthii strain, a L. jordanis strain and a L. gormanii strain.
A further embodiment of the invention is method for modulating metabolism of atypical upper respiratory pathogenic bacteria comprising the step of contacting atypical upper respiratory pathogenic bacteria with an antibacterially effective amount of a composition comprising a compound selected from the group consisting of: gemifloxacin, ofloxacin, levofloxacin, trovafloxacin, azithromycin, moxifloxacin, ciprofloxacin, clarithromycin, rifampicin and erythromycin; or an antibacterially effective derivative of any of these compounds.
A still further embodiment of the invention is a method of treating or preventing a bacterial infection by atypical upper respiratory pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a compound selected from the group consisting of: gemifloxacin, ofloxacin, levofloxacin, trovafloxacin, azithromycin, moxifloxacin, ciprofloxacin, clarithromycin, rifampicin and erythromycin; or an antibacterially effective derivative of any of these compounds, to a mammal suspected of having or being at risk of having an infection with atypical upper respiratory pathogenic bacteria.
It is preferred in the methods of the invention that said contacting is performed once daily.
Various changes and modifications within the spirit and scope of the disclosed invention will become readily apparent to those skilled in the art from reading the following descriptions and from reading the other parts of the present disclosure.
The present invention provides, among other things, methods for using a composition comprising a gemifloxacin compound against atypical upper respiratory pathogenic bacteria, especially a member of the genus Legionella, a member of the genus, Pseudomonas, Pseudomonas aeruginosa strain, a L. pneumophila strain, a L. pneumophila serogroup 1, a L. pneumophila serogroup 2, a L. pneumophila serogroup 3, a L. pneumophila serogroup 4, a L. pneumophila serogroup 5, a L. pneumophila serogroup 6, a L. pneumophila serogroup 7, a L. pneumophila serogroup 8, a L. dumoffii strain, a L. longbeacheae strain, a L. micdadei strain, a L. oakridgensis strain, a L. feelei strain, a L. anisa strain, a L. sainthelensi strain, a L. bozemanii strain, a L. gormanii strain, a L. wadsworthii strain, a L. jordanis strain or a L. gormanii strain.
As used herein xe2x80x9cgemifloxacin compound(s)xe2x80x9d means a compound having antibacterial activity described in patent application PCT/KR98/00051 published as WO 98/42705, or patent application EP 688772.
This invention was based, in part, on analyses evaluating the in vitro activity and postantibiotic effect (herein xe2x80x9cPAExe2x80x9d) of gemifloxacin compared with those of trovafloxacin, moxifloxacin, grepafloxacin, levofloxacin, ofloxacin, ciprofloxacin, azithromycin, clarithromycin, erythromycin and rifampicin against isolates of Legionella pneumophila and other Legionella spp. Test isolates included L. pneumophila serogroup 1-12 (204), L. dumoffii (10), L. micdadei (10) and L. longbeacheae (7). The PAE was determined by exposing the isolates to the test antimicrobials for 1 hour at four times the minimum inhibitory concentration (herein xe2x80x9cMICxe2x80x9d). The antimicrobial was removed by three consecutive centrifugations into fresh broth. The PAE was calculated by measuring bacterial growth kinetics in similar antimicrobial-free cultures. Rifampicin and trovafloxacin were the most active agents tested (MIC90xe2x89xa60.008 mg/L). Gemifloxacin displayed high potency (MIC90 0.016 mg/L) which was comparable to levofloxacin, grepafloxacin and moxifloxacin (MIC90 0.016 mg/L) and more active than ciprofloxacin and ofloxacin (MIC90 0.03 mg/L). Against L. dumoffii and L. longbeachae, gemifloxacin (MIC90 0.06 mg/L) was as active than ciprofloxacin, ofloxacin, grepafloxacin and moxifloxacin. Against erythromycin-resistant L. pneumophila, gemifloxacin showed the longest PAE at 4.65 hours, compared with 4.18 hours for grepafloxacin, 3.38 hours for moxifloxacin and 2.83 hours for trovafloxacin. The gemifloxacin PAE was significantly superior to that of rifampicin (0.9 h), clarithromycin (1.9 h) and levofloxacin (2.59 h). Against erythromycin-susceptible L. pneumophila only gemifloxacin, moxifloxacin, levofloxacin, ofloxacin and ciprofloxacin had a PAE over 3 hours. For erythromycin-resistant Legionella spp. other than L. pneumophila, gemifloxacin, moxifloxacin, levofloxacin and ofloxacin had PAEs in excess of 3 hour, which was significantly longer than the PAE of ciprofloxacin grepafloxacin and erythromycin. The half-life for gemifloxacin and the data presented here indicate a significant PAE to support a once-daily administration of this agent for the treatment of Legionella infections, and this dosing is preferred in the methods of the invention.
The MIC range of gemifloxacin against L. pneumophila serogroups 1-9 was 0.008-0.06 mg/L (Tables 2 and 3). Gemifloxacin was 5-6-fold more active than erythromycin against L. pneumophila strains tested. Gemifloxacin activity against L. pneumophila strains was higher than ciprofloxacin and ofloxacin but similar to grepafloxacin and moxifloxacin.
L. pneumophila strains of serogroups 1-3 and 7-9 were more susceptible to gemifloxacin than L. pneumophila serogroups 4-6. Against the most frequent L. pneumophila, such as serogroup 1, gemifloxacin MIC90 (0.016 mg/L) was superior to azithromycin, clarithromycin, erythromycin, ofloxacin and ciprofloxacin.
Against L. dumoffii and L. longbeacheae, gemifloxacin, grepafloxacin and clarithromycin showed superior activity to azithromycin and erythromycin (Table 4). Against L. micdadei, gemifloxacin, ciprofloxacin, ofloxacin and moxifloxacin MICs were 5-fold more active than erythromycin.
Against erythromycin-resistant L. pneumophila only gemifloxacin, moxifloxacin and grepafloxacin displayed a mean PAE of  greater than 3 hours (Table 5). Clarithromycin, erythromycin and rifampicin showed a PAE of  less than 2 hours against these strains. Against erythromycin-resistant Legionella spp. other than pneumophila, gemifloxacin, grepafloxacin, levofloxacin, ofloxacin and rifampicin displayed a mean PAE of  greater than 3 hours, and erythromycin and clarithromycin of  less than 2 hours.
Against erythromycin-susceptible L. pneumophila, gemifloxacin, moxifloxacin, ofloxacin and ciprofloxacin displayed a mean PAE of  greater than 3 hours. Gemifloxacin and ofloxacin were the only quinolones showing a mean PAE of  greater than 2 hours against erythromycin-susceptible Legionella spp. other than L. pneumophila. 
Gemifloxacin is an effective antimicrobial agent against most Legionella spp. and was significantly superior to the commonly used legionellosis therapy, erythromycin.
Against erythromycin-susceptible L. pneumophila, the mean PAE of gemifloxacin (3.49 hours) was xe2x89xa71 h longer than that of trovafloxacin, levofloxacin and clarithromycin.
Against erythromycin-susceptible Legionella spp. other than pneumophila the mean PAE of gemifloxacin (2.27 hours) was xe2x89xa71 h longer than that of trovafloxacin, moxifloxacin and clarithromycin.
Against erythromycin-resistant L. pneumophila, the mean PAE of gemifloxacin (4.65 hours) was significantly superior to the mean PAE of trovafloxacin, levofloxacin, ciprofloxacin, azithromycin, clarithromycin, erythromycin and rifampicin. A difference in mean PAE was also noted between gemifloxacin and trovafloxacin against Legionella spp. other than L. pneumophila. 
The results of this study indicate that gemifloxacin should be a promising agent for the treatment of lower respiratory tract infections caused by Legionella spp.
The invention provides a method for modulating metabolism of atypical upper respiratory pathogenic bacteria. Skilled artisans can readily choose atypical upper respiratory pathogenic bacteria or patients infected with or suspected to be infected with these organisms to practice the methods of the invention. Alternatively, the bacteria useful in the methods of the invention may be those described herein.
The contacting step in any of the methods of the invention may be performed in many ways that will be readily apparent to the skilled artisan. However, it is preferred that the contacting step comprises provision of a composition comprising a gemifloxacin compound to a mammal, particularly a human patient in need of such composition or directly to bacteria in culture medium or buffer or on a surface.
For example, when contacting a human patient or contacting said bacteria in a human patient or in vitro, the compositions comprising a gemifloxacin compound, preferably pharmaceutical compositions may be administered in any effective, convenient manner including, for instance, administration by topical, oral, anal, vaginal, intravenous, intraperitoneal, intramuscular, subcutaneous, intranasal or intradermal routes among others.
It is also preferred that these compositions be employed in combination with a non-sterile or sterile carrier or carriers for use with cells, tissues or organisms, such as a pharmaceutical carrier suitable for administration to a subject. Such compositions comprise, for instance, a media additive or a therapeutically effective amount of a compound of the invention, preferably a gemifloxacin compound, and a pharmaceutically acceptable carrier or excipient. Such carriers may include, but are not limited to, saline, buffered saline, dextrose, water, glycerol, ethanol and combinations thereof. The formulation should suit the mode of administration.
Gemifloxacin compounds and compostions of the methods of the invention may be employed alone or in conjunction with other compounds, such as bacterial efflux pump inhibtor compounds or antibiotic compounds, particularly non-quinolone compounds, e.g., beta-lactam antibiotic compounds.
In therapy or as a prophylactic, the active agent of a method of the invention is preferably administered to an individual as an injectable composition, for example as a sterile aqueous dispersion, preferably an isotonic one.
Alternatively, the gemifloxacin compounds or compositions in the methods of the invention may be formulated for topical application for example in the form of ointments, creams, lotions, eye ointments, eye drops, ear drops, mouthwash, impregnated dressings and sutures and aerosols, and may contain appropriate conventional additives, including, for example, preservatives, solvents to assist drug penetration, and emollients in ointments and creams. Such topical formulations may also contain compatible conventional carriers, for example cream or ointment bases, and ethanol or oleyl alcohol for lotions. Such carriers may constitute from about 1% to about 98% by weight of the formulation; more usually they will constitute up to about 80% by weight of the formulation.
For administration to mammals, and particularly humans, it is expected that the antibacterially effective amount is a daily dosage level of the active agent from 0.001 mg/kg to 10 mg/kg, typically around 0.1 mg/kg to 1 mg/kg, preferably about1 mg/kg. A physician, in any event, will determine an actual dosage that is most suitable for an individual and will vary with the age, weight and response of the particular individual. The above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention. It is preferred that the dosage is selected to modulate metabolism of the bacteria in such a way as to inhibit or stop growth of said bacteria or by killing said bacteria. The skilled artisan may identify this amount as provided herein as well as using other methods known in the art, e.g. by the application MIC tests.
A further embodiment of the invention provides for the contacting step of the methods to further comprise contacting an in-dwelling device in a patient. In-dwelling devices include, but are not limited to, surgical implants, prosthetic devices and catheters, i.e., devices that are introduced to the body of an individual and remain in position for an extended time. Such devices include, for example, artificial joints, heart valves, pacemakers, vascular grafts, vascular catheters, cerebrospinal fluid shunts, urinary catheters, and continuous ambulatory peritoneal dialysis (CAPD) catheters.
A gemifloxacin compound or composition of the invention may be administered by injection to achieve a systemic effect against relevant bacteria, preferably a atypical upper respiratory pathogenic bacteria, shortly before insertion of an in-dwelling device. Treatment may be continued after surgery during the in-body time of the device. In addition, the composition could also be used to broaden perioperative cover for any surgical technique to prevent bacterial wound infections caused by or related to atypical upper respiratory pathogenic bacteria.
In addition to the therapy described above, a gemifloxacin compound or composition used in the methods of this invention may be used generally as a wound treatment agent to prevent adhesion of bacteria to matrix proteins, particularly atypical upper respiratory pathogenic bacteria, exposed in wound tissue and for prophylactic use in dental treatment as an alternative to, or in conjunction with, antibiotic prophylaxis.
Alternatively, a gemifloxacin compound or composition of the invention may be used to bathe an indwelling device immediately before insertion. The active agent will preferably be present at a concentration of 1 xcexcg/ml to 10 mg/ml for bathing of wounds or indwelling devices.
Also provided by the invention is a method of treating or preventing a bacterial infection by atypical upper respiratory pathogenic bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a gemifloxacin compound to a mammal, preferably a human, suspected of having or being at risk of having an infection with atypical upper respiratory pathogenic bacteria.
While a preferred object of the invention provides a method wherein said atypical upper respiratory pathogenic bacteria is selected from the group consisting of: a member of the genus Legionella, a member of the genus, Pseudomonas, Pseudomonas aeruginosa strain, a L. pneumophila strain, a L. pneumophila serogroup 1, a L. pneumophila serogroup 2, a L. pneumophila serogroup 3, a L. pneumophila serogroup 4, a L. pneumophila serogroup 5, a L. pneumophila serogroup 6, a L. pneumophila serogroup 7, a L. pneumophila serogroup 8, a L. dumoffii strain, a L. longbeacheae strain, a L. micdadei strain, a L. oakridgensis strain, a L. feelei strain, a L. anisa strain, a L. sainthelensi strain, a L. bozemanii strain, a L. gormanii strain, a L. wadsworthii strain, a L. jordanis; strain and a L. gormanii strain. Other atypical upper respiratory pathogenic bacteria may also be included in the methods. The skilled artisan may identify these organisms as provided herein as well as using other methods known in the art, e.g. MIC tests.